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Immunomodulatory Effects of a Rationally Designed Peptide Mimetic of Human Ifnβ in Eae Model of Multiple Sclerosis Publisher Pubmed



Poorebrahim M1 ; Asghari M2 ; Abazari MF3 ; Askari H4 ; Sadeghi S1 ; Taherikafrani A5 ; Nasresfahani MH2 ; Ghoraeian P6 ; Aleagha MN3 ; Arab SS7 ; Kennedy D8 ; Montaseri A9 ; Mehranfar M10 ; Sanadgol N11
Authors
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Authors Affiliations
  1. 1. Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
  2. 2. Department of Molecular Biotechnology, Cell Science Research Center, Royan Institute of Biotechnology, ACECR, Isfahan, Iran
  3. 3. Department of Genetics, Islamic Azad University, Tehran Medical Branch, Tehran, Iran
  4. 4. Department of Physiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
  5. 5. Department of Biotechnology, Faculty of Advanced Sciences and Technologies, University of Isfahan, Isfahan, 81746-73441, Iran
  6. 6. Department of Genetics, Tehran Medical Sciences Branch, Islamic Azad University, Tehran, Iran
  7. 7. Department of Biophysics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
  8. 8. GRIDD Griffith Institute for Drug Discovery, Griffith University, Brisbane, Queensland, Australia
  9. 9. Department of Anesthesiology and Intensive Care, Imam Khomeini Medical Center, Tehran University of Medical Sciences, Tehran, Iran
  10. 10. Pasteur Institute of Iran, Biotechnology research center, Tehran, Iran
  11. 11. Department of Biology, Faculty of Sciences, University of Zabol, Zabol, Iran

Source: Progress in Neuro-Psychopharmacology and Biological Psychiatry Published:2018


Abstract

The efficiency of interferon beta (IFNβ)-based drugs is considerably limited due to their undesirable properties, especially high immunogenicity. In this study, for the first time we investigated the impact of a computationally designed peptide mimetic of IFNβ called MSPEP27, in the animal model of MS. A peptide library was constructed using the Rosetta program based on the predominant IFNAR1-binding site of IFNβ. Molecular docking studies were carried out using ClusPro and HADDOCK tools. The GROMACS package was subsequently used for molecular dynamics (MD) simulations. Validation of peptide-receptor interaction was carried out using intrinsic fluorescence measurements. To explore in silico findings further, experimental autoimmune encephalomyelitis (EAE) was induced by subcutaneous immunization of myelin oligodendrocyte glycoprotein (MOG35-55). Mice were then separated into distinct groups and intravenously received 10 or 20 mg kg− 1 of MSPEP27 or IFNβ. The inflammatory mediators were monitored by immunohistochemistry (IL17, CD11b, CD45), quantitative real-time PCR (MMP2, MMP9, TIMP-1) and enzyme-linked immunosorbent assay (IL1β TNFα) methods. Among the library of tolerated peptides, MSPEP27, a peptide with favorable physicochemical properties, was chosen for further experiments. This peptide was shown to significantly interact with IFNAR1 in a dose-dependent manner. Like IFNβ MSPEP27 could efficiently bind to IFNAR1 and form a stable peptide-receptor complex during 30 ns MD simulations. In vivo analyses revealed that MSPEP27 could lessen inflammation by modulating the levels of inflammatory mediators. According to our results, MSPEP27 peptide could efficiently bind to IFNAR1 and suppress neuroinflammation in vivo. We conclude that MSPEP27 has protective effects against MOG-induced EAE via reduction of immune dysfunction and inflammation. © 2017 Elsevier Inc.
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